Fused pentacyclic imidazole derivatives as modulators of TNF activity

Abstract

A series of substituted fused pentacyclic benzimidazole derivatives, and analogues thereof, being potent modulators of human TNFα activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

The invention claimed is: 
     
       1. A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 A represents N or C—R 6 ; 
 B represents N or C—R 7 ; 
 D represents N or C—R 8 ; 
 Z represents methylene; 
 E represents a fused heteroaromatic ring system selected from the groups of formula (Ea), (Eb) and (Ec): 
 
       
         
           
           
               
               
           
         
       
       wherein the asterisks (*) represent the site of attachment of E to the remainder of the molecule;
 R 1  represents hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, —OR a , —SR a , —SOR a , —SO 2 R a , —NR b R c , —NR c COR d , —NR c CO 2 R d , —NHCONR b R c , —NR b SO 2 R e , —COR d , —CO 2 R d , —CONR b R c , —SO 2 NR b R c , or —S(O)(N—R b )R e ; or R 1  represents C 1-6  alkyl, C 3-7  cycloalkyl, C 4-7  cycloalkenyl, aryl, aryl(C 1-6 )alkyl, C 3-7  heterocycloalkyl, C 3-7  heterocycloalkenyl, heteroaryl, heteroaryl(C 1-6 )alkyl, (C 3-7 )heterocycloalkyl(C 1-6 )alkyl-aryl-, (C 3-7 )heterocycloalkenyl-aryl-, (C 3-7 )cycloalkyl-heteroaryl-, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-heteroaryl-, (C 4-7 )cycloalkenyl-heteroaryl-, (C 4-9 )bicycloalkyl-heteroaryl-, (C 3-7 )heterocycloalkyl-heteroaryl-, (C 3-7 )heterocycloalkyl(C 1-6 )alkyl-heteroaryl-, (C 3-7 )heterocycloalkenyl-heteroaryl-, (C 4-9 )heterobicycloalkyl-heteroaryl- or (C 4-9 )spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one, two or three substituents independently selected from halogen, halo(C 1-6 )alkyl, cyano, cyano(C 1-6 )alkyl, nitro(C 1-6 )alkyl, C 1-6  alkyl, phosphate(C 1-6 )alkyl, (C 1-6 )alkylphosphate(C 1-6 )alkyl, phosphate(C 1-6 )alkoxy(C 1-6 )alkyl, sulphate(C 1-6 )alkyl, difluoromethyl, trifluoromethyl, trifluoroethyl, C 2-6  alkenyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 6  alkoxy, (C 1-6 )alkoxy(C 1-6 )-alkyl, trifluoroethoxy, carboxy(C 3-7 )cycloalkyloxy, C 1-6  alkylthio, C 1-6  alkylsulphonyl, 
 
       (C 1-6 )alkylsulphonyl(C 1-6 )alkyl, oxo, amino, amino(C 1-6 )alkyl, C 1-6  alkylamino, di(C 1-6 )-alkylamino, di(C 1-6 )alkylamino(C 1-6 )alkyl, (C 1-6 )alkoxy(C 1-6 )alkylamino, N—[(C 1-6 )alkyl]-N-[hydroxy(C 1-6 )alkyl]amino, (C 2-6 )alkylcarbonylamino(C 1-6 )alkyl, (C 2-6 )alkoxycarbonyl-amino(C 1-6 )alkyl, C 1-6  alkylsulphinylamino, C 1-6  alkylsulphonylamino, N—[(C 1-6 )alkyl]-N—[(C 1-6 )alkylsulphonyl]amino, bis[(C 1-6 )alkylsulphonyl]amino, (C 1-6 )alkylsulphonylamino-(C 1-6 )alkyl, N—[(C 1-6 )alkyl]-N-[carboxy(C 1-6 )alkyl]amino, carboxy(C 3-7 )cycloalkylamino, carboxy(C 3-7 )cycloalkyl(C 1-6 )alkylamino, imino, formyl, C 2-6  alkylcarbonyl, (C 2-6 )alkyl-carbonyloxy(C 1-6 )alkyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6  alkoxycarbonyl, C 2-6  alkoxy-carbonyl(C 1-6 )alkyl, morpholinyl(C 1-6 )alkoxycarbonyl, C 2-6  alkoxycarbonylmethylidenyl, aminocarbonyl, aminosulphonyl, (C 1-6 )alkylsulphoximinyl and [(C 1-6 )alkyl][N—(C 1-6 )-alkyl]sulphoximinyl;
 R 2  represents hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy or —OR a ; or R 2  represents C 1-6  alkyl or heteroaryl, either of which groups may be optionally substituted by one, two or three substituents independently selected from hydroxy(C 1-6 )alkyl and C 2-6  alkoxycarbonyl; 
 R 3  and R 4  independently represent hydrogen, halogen or trifluoromethyl; or C 1-6  alkyl; 
 R 5  represents hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, —OR a  or C 1-6  alkylsulphonyl; or R 5  represents C 1-6  alkyl; 
 R 6 , R 7  and R 8  independently represent hydrogen, halogen, trifluoromethyl, C 1-6  alkyl or C 1-6  alkoxy; 
 R 12  represents hydrogen or C 1-6  alkyl; 
 R a  represents C 1-6  alkyl, C 3-7  cycloalkyl, aryl, aryl(C 1-6 )alkyl, C 3-7  heterocycloalkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents selected from C 1-6  alkoxy and oxo; 
 R b  represents hydrogen or trifluoromethyl; or C 1-6  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7  heterocycloalkyl, C 3-7  heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents selected from C 1-6  alkoxy, C 1-6  alkylthio, C 1-6  alkylsulphinyl, C 1-6  alkylsulphonyl, hydroxy, cyano, C 2-6  alkoxycarbonyl, 6)alkylamino and C 2-6  alkoxycarbonylamino; 
 R c  represents hydrogen or trifluoromethyl; or C 1-6  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7  heterocycloalkyl, C 3-7  heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents selected from C 2-6  alkylcarbonyl and C 2-6  alkoxycarbonyl; or 
 R b  and R c , when taken together with the nitrogen atom to which they are both attached, represent a heterocyclic moiety selected from azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl, homopiperazin-1-yl, (imino)(oxo)thiazinan-4-yl, (oxo)thiazinan-4-yl and (dioxo)-thiazinan-4-yl, any of which groups may be optionally substituted by one or more substituents selected from C 1-6  alkyl, C 1-6  alkylsulphonyl, hydroxy, hydroxy(C 1-6 )alkyl, amino(C 1-6 )alkyl, cyano, oxo, C 2-6  alkylcarbonyl, carboxy, C 2-6  alkoxycarbonyl, amino, C 2-6  alkylcarbonyl-amino, C 2-6  alkylcarbonylamino(C 1-6 )alkyl, C 2-6  alkoxycarbonylamino, C 1-6  alkyl-sulphonylamino and aminocarbonyl; 
 R d  represents hydrogen; or R d  represents C 1-6  alkyl, C 3-7  cycloalkyl, aryl, C 3-7  heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents selected from halogen, C 1-6  alkyl, C 1-6  alkoxy, oxo, C 2-6  alkylcarbonyloxy and di(C 1-6 )alkylamino; 
 R e  represents C 1-6  alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by C 1-6  alkyl; and 
 R f  and R g  independently represent hydrogen or C 1-6  alkyl. 
 
     
     
       2. The compound as claimed in  claim 1  wherein A represents C—R 6 , B represents 
       C—R 7 , and D represents C—R 8 . 
     
     
       3. The compound as claimed in  claim 1  represented by formula (IIA) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R f  and R g  are as defined in  claim 1 . 
     
     
       4. The compound as claimed in  claim 3  represented by formula (IIA-1) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 W represents N, CH or CF; 
 R 9  represents hydroxy(C 1-6 )alkyl or amino(C 1-6 )alkyl; and 
 R 10  represents hydrogen or C 1-6  alkyl. 
 
     
     
       5. The compound as claimed in  claim 1  selected from the group consisting of
 (7R,14R)-1-(Difluoromethoxy)-10-fluoro-5-imino-11-[2-(2-hydroxypropan-2-yl)-pyrimidin-5-yl]-7,14-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocine; 
 (7R,14R)-11-Chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b]-[2,5]benzodiazocin-5(14H)-imine hydrochloride; and 
 2-{5-[(5Z,7R,14R)-1-(Difluoromethoxy)-5-(methylimino)-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl]propan-2-ol. 
 
     
     
       6. A pharmaceutical composition comprising a compound of formula (I) as defined in  claim 1  or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier. 
     
     
       7. The pharmaceutical composition as claimed in  claim 6  further comprising an additional pharmaceutically active ingredient. 
     
     
       8. A method for the treatment of an inflammatory or autoimmune disorder, wherein the inflammatory or autoimmune disorder is rheumatoid arthritis or Crohn's disease, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in  claim 1  or an N-oxide thereof, or a pharmaceutically acceptable salt thereof. 
     
     
       9. The compound as claimed in  claim 2  wherein:
 R 1  represents halogen; or R 1  represents heteroaryl, which group may be optionally substituted by one, two or three substituents independently selected from halogen, cyano, C 1-6  alkyl, difluoromethyl, hydroxy(C 1-6 )alkyl, oxo, amino and amino(C 1 -6)alkyl; 
 R 2  represents hydrogen or halogen; 
 R 3  represents hydrogen, halogen or C 1-6  alkyl; 
 R 4  represents hydrogen, halogen or C 1-6  alkyl; 
 R 5  represents difluoromethoxy or —OR a ; 
 R 6  represents hydrogen, halogen or trifluoromethyl; 
 R 7  represents hydrogen or trifluoromethyl; 
 R 8  represents hydrogen or trifluoromethyl; 
 R 12  represents hydrogen; 
 R a  represents C 1-6  alkyl, aryl(C 1-6 )alkyl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents selected from C 1-6  alkoxy and oxo; 
 R f  represents hydrogen or methyl; and 
 R g  represents hydrogen or methyl.